Long-term treatment with anti-alpha 4 integrin antibodies aggravates colitis in G alpha i2-deficient mice

Targeted deletion of the heterotrimeric G protein, Galphai2, in mice induces lethal colitis closely resembling ulcerative colitis. In chronic colitis, migration of circulating leukocytes into the intestinal mucosa is partially dependent on alpha4 integrins. In previous studies, short-term administration of anti-alpha4 integrin antibodies has been shown to attenuate intestinal inflammation, and here we elucidate the effect of long-term administration of anti-alpha4 integrin antibodies on colitis in Galphai2(-/- )mice. Long-term blockade of alpha4 integrin significantly increased the severity of colitis in Galphai2(-/-) mice. The inflammation was confined to the colon, associated with increased cancer in situ, destruction of crypt architecture, and increased production of IL-1beta, TNF-alpha and IFN-gamma. Blockade of alpha4 integrin reduced the recruitment of activated T cells to the small intestine. In strong contrast, there were significantly higher numbers of activated T cells in the colonic lamina propria and epithelium, most probably due to in situ proliferation. Furthermore, treatment with alpha4 integrin antibodies induced decreased levels of total IgA and IgG in sera, whereas total IgM levels were unchanged. These new findings may have implications in the understanding of the progression of chronic intestinal inflammation.     

Ionic conductances of cultured principal cell epithelium of renal collecting duct

The ionic conductive properties were studied of epithelia of collecting duct principal cells which had been grown in primary tissue culture from renal cortex/capsule explants. When pretreated with aldosterone (10^–6 mol/l) and bathed on either surface with isotonic HCO ₃ ^– -free Ringer's solution, the transepithelial voltage,V _te, varied between –21 and –72 mV (apical surface negative) while the transepithelial resistance,R _te, ranged from 0.4 to 1.5 kcm². By 10:1 step-changes in Na⁺ concentration the apical cell membrane was shown to have a high conductivity for sodium, inhibitable by amiloride, 10^–6 mol/l. However, contrary to observations in natural collecting duct under control conditions, amiloride never reversed the polarity ofV _te even at 10^–4 mol/l. Both the apical and the basolateral cell membranes were conductive for potassium and both conductivities were inhibitable by Ba²⁺ (5 mmol/l). 10:1 reduction of apical Cl^– concentration strongly hyperpolarizedV _te with a monophasic time course suggesting the presence of a paracellular shunt conductance for Cl^–. In addition there may be a small Cl^– conductance present in the apical cell membrane since apical application of the chloride channel blocker 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPAB) at 10^–7 mol/l produced a minute but significant hyperpolarization. On the other hand, 10:1 reduction of basolateral Cl^– concentration caused a biphasic change inV _te (initial depolarization, followed by repolarization) which indicates the presence of a large Cl^– conductance in the basolateral cell membrane. The latter was not inhibitable by 10^–7 mol/l NPPAB. Higher concentrations of this and of an other Cl^– channel blocker produced non-specific effects. In conclusion, our studies of a pure principal cell epithelium confirm findings described for the intact cortical collecting duct and add new information concerning chloride conductivity and related blocking agents.Dedicated to Prof. Dr. H. Sitte, Homburg, FRG, upon his 60th birthday.     

Radical prostatectomy: lower rates among African-American men.

This study compares radical prostatectomy rates by race among male Medicare patients in New York. A retrospective analysis was conducted of all radical prostatectomies performed on hospitalized male Medicare beneficiaries for the period 1991 through 1993. Basic trend data also were analyzed for 1990. Pattern analysis was conducted on the 4154 procedures performed between 1990 and 1993. The rate of radical prostatectomy rose dramatically during the 3-year period from 1990 to 1992 among New York''s 1.1 million male Medicare beneficiaries. The rates rose for both African Americans and whites. However, the annual rates of radical prostatectomy for African Americans were significantly below those for whites. Lower rates of radical prostatectomies were observed for African Americans in all age groups except the < 65-year-old group. However, the total number of radical prostatectomies in this age group were small in number. An important finding was the lower annual rates of radical prostatectomy for African Americans in the 65- to 69-year-old age group. During the period under study, prostate cancer among Medicare patients in New York rose by 33.8% for African Americans and 26.5% for whites. Significantly, local disease was found at the time of diagnosis in 70% of whites but in only 55% of African Americans. These data reflect later stage at diagnosis among African-American males. These results indicate that despite higher national rates for prostate cancer, male African-American Medicare patients in New York have reduced access to radical prostatectomy as a treatment modality. This is especially of importance in the < 70-year-old group in whom most authorities consider the procedure appropriate. The reasons for this reduced access are discussed as are the measures needed to remedy the underlying inequities in health care.     

The time course of cross-talk during the simultaneous specification of bimanual movement amplitudes

 We investigated the time course of the amplitude specification of rapid bimanual reversal movements (lateral displacements on two digitizers). To this end we used the timed-response paradigm in which the response has to be initiated synchronously with an auditory signal. Information about the required amplitudes was presented at various times before the synchronization signal. Consistent with previous results, the progression of amplitude specification was reflected in the dependence of the amplitudes of the reversal movements on the time interval between amplitude information and synchronization signal. Same or different amplitudes for the hands were used to examine cross-talk at the programming level of the two-level model of intermanual interference. The results indicate the existence of cross-talk in particular at short intervals between information about amplitude and movement initiation. This is consistent with the notion that cross-talk between concurrent processes of amplitude specification is transient and vanishes as the time available for motor programming increases. Received: 28 August 1996 / Accepted: 10 July 1997     

Localization of the chromosomal breakpoints of the t(12;16) in liposarcoma to subbands 12q13.3 and 16p11.2

Short-term cultures of two myxoid liposarcomas and two mixed-type (myxoid and round cell) liposarcomas were cytogenetically analyzed. A t(12;16)(q13;p11) was present in three tumors, whereas the fourth had an unbalanced 12;16-translocation with breaks in 12q13 and 12q22, with loss of the 12q13-q22 segment, and in 16p11. In the two mixed liposarcomas, the breakpoints could be determined at subband level to 12q13.3 and 16p11.2.     

Acellular Bordetella pertussis vaccine enhances mucosal interleukin-10 production, induces apoptosis of activated Th1 cells and attenuates colitis in Galphai2-deficient mice

Mice deficient for the inhibitory G protein subunit alpha2 (Galphai2(-/-)) spontaneously develop a progressive inflammatory bowel disease resembling ulcerative colitis, and have a T helper 1 (Th1)-dominated immune response prior to onset of colitis, which is further augmented after the onset of disease. The present study was performed to investigate whether the Galphai2(-/-) mice were able to down-regulate the Th1-dominated inflammatory mucosal immune response and/or induce an anti-inflammatory Th2/T regulatory response and thereby diminish the severity of colitis following treatment with acellular Bordetella pertussis vaccine. The acellular vaccine against B. pertussis, the causative agent of whooping cough, has been demonstrated to induce a Th2-mediated response in both man and mice. We therefore treated Galphai2(-/-) mice intraperitoneally with a three-component acellular B. pertussis vaccine. The treated Galphai2(-/-) mice showed significantly increased interleukin (IL)-10 production in intestinal tissue, associated with significantly reduced colitis and decreased mortality, compared to untreated Galphai2(-/-) mice. The attenuation of colitis in Galphai2(-/-) mice was due, at least partly, to the B. pertussis surface antigen filamentous haemagglutinin (FHA), which almost completely inhibited proliferation of CD4(+) T cells and stimulated apoptosis of activated CD4(+) T helper 1 cells. In conclusion, the three-component acellular B. pertussis vaccine containing filamentous haemagglutinin increases the production of IL-10 in the intestinal mucosa, induces apoptosis of activated Th1 cells and attenuates colitis in Galphai2(-/-) mice.     

Chromosomal abnormalities in giant cell tumors of bone.

Cytogenetic analysis of short-term cultures from ten giant cell tumors of bone revealed clonal and nonclonal chromosome abnormalities in three tumors and nonclonal changes only in seven. None of the clonal aberrations, inv(21)(p11q21) in one tumor, +5 in another, and t(15q22q), dic(4;22)(p16;p1?), double minutes, dicentrics, and ring chromosomes present in three separate clones in the third tumor, were identical to previously reported clonal changes in giant cell tumors. Telomeric associations were found in five tumors. The telomeres of chromosome arms 19q and 15p were particularly frequently involved.